Project Summary Abstract Building on our 25-year track record in comprehensive genomic studies and addressing NHGRI's goal for this RFA, we propose to create, apply and test a powerful, reliable and general strategy for ?comprehensive? identification of risk and protective variants that contribute significantly to any common disease of interest. Toward this end, we will: Create a Common Disease Consortium (CDC) that brings together a collaborative network of investigators with deep clinical and genetic expertise and >1.1 million well-characterized samples (cases and controls) across diverse populations, including Europeans, African Americans, Hispanics and Asians. The CDC will undertake genetic studies under three major projects related to: (1) Five systemic diseases ? early-onset coronary artery disease, type 2 diabetes, inflammatory bowel disease, atrial fibrillation, and stroke; (2) Three severe neurological disorders ? autism, schizophrenia and epilepsy; and (3) Two countries with special advantages for genetic studies ? Finland and Estonia. Through these three projects, the CDC will explore a range of study designs, population-genetic strategies, genetic architectures, and diverse populations. Sequence 450,000 samples from the CDC, using the expertise of the Broad Institute's genomics platform to generate high quality data and to drive down sequencing costs. Analyze the sequence data to elucidate the genetic basis of the diseases, by applying state- of-the-art methods from in our preliminary studies and developing new methods to increase power to detect association. Create, disseminate and share data, tools, and resources, to enable the scientific community to access and analyze genetic studies from the CDC and other sources.